Post nirmatrelvir/ritonavir erythema multiforme in a patient with coronavirus disease infection

ABSTRACT Erythema multiforme (EM), an immune-mediated skin condition, can occur after infection or following the use of medications. In this study, we describe a patient who developed EM after nirmatrelvir/ritonavir administration. An 81-year-old woman presented with fever and dyspnea. Laboratory investigations showed positive coronavirus disease (COVID-19) based on polymerase chain reaction assay, and she received a 5-day regimen of nirmatrelvir/ritonavir. We observed development of EM after this treatment and initiated prednisone (1 mg/kg) therapy, which led to rapid improvement. Our study is the first to report EM in a patient with COVID-19, who received nirmatrelvir/ritonavir and showed a favorable response.


INTRODUCTION
Erythema multiforme (EM), an immune-mediated condition involving the skin and mucous membranes 1,2 , has an estimated prevalence of less than 1% 3 . EM predominantly affects women and adults aged 20-40 years 1 . The pathophysiology of this condition involves the production of immunocomplexes, which can be precipitated by infections or medications and injure small vessels in the skin and mucous membranes 4 . Lesions may be asymptomatic or may present with dysesthesia, and the mean duration varies from 1 to 4 weeks. EM is characterized by target lesions, which may present as macules, papules, or vesicles, mainly distributed on the hands, feet, knees, and elbows 1,5 . Treatment involves withdrawal of the possible causative agent in addition to corticosteroid therapy 1 .
Coronavirus disease (COVID-19), an infection caused by the severe acute respiratory syndrome coronavirus 2 6 may present with cutaneous manifestations 7 . Antiviral medications, including nirmatrelvir/ritonavir are approved for treatment in patients at risk of adverse clinical evolution 8 .
In this article, we describe a patient who developed EM after nirmatrelvir/ritonavir administration.

CASE REPORT
We searched the MEDLINE database via PubMed without any time restrictions. The following descriptors (bold), synonyms, natural language, and Boolean operators were used to cross-  An 81-year-old woman was admitted for evaluation of cough, fever, and mild dyspnea, which required supplemental oxygen inhaler use. COVID-19 polymerase chain reaction assay showed positive results 3 days after the onset of symptoms. Nirmatrelvir/ritonavir therapy was initiated 4 days after onset of symptoms and was continued for 5 days. An acute cutaneous eruption of reddish annular macules suggestive of EM was observed on the patient's arms the day following completion of the medication regimen (Figures 1 and 2). Histopathological examination of the lesions was not performed. Prednisone (1 mg/kg) therapy was initiated, which led to rapid improvement.

DISCUSSION
To our knowledge, this is the first report of EM that showed a positive outcome in a patient with COVID-19, who was treated with nirmatrelvir/ritonavir.
Previous studies have reported EM after COVID-19 and lopinavir/ritonavir administration 9 . Likewise, EM associated with COVID-19 has been described in the medical literature, both in patients aged <30 years and in those aged >55 years 7 .
Our patient did not undergo histopathological examination; however, the temporal relationship between the appearance of the lesion after medication initiation and improvement after discontinuation of therapy reinforces the contribution of nirmatrelvir/ritonavir to EM in this case. The Naranjo Adverse Drug Reaction Probability Scale 10 score in our patient was 5, which indicates a probable adverse reaction and strengthens our suspicion.
We could not differentiate whether EM was due to a viral infection or secondary to the use of the aforementioned medications in our patient, which serves as a limitation of this study.

CONCLUSIONS
In this case report, we describe a rare skin reaction following the use of nirmatrelvir/ritonavir. Our findings will serve as guidelines for early detection of this complication and can aid with the establishment of the most suitable treatment in such cases.